title: Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy.
abstract: Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria.
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Johanna
authors.initials: J
authors.lastname: Guzman
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Jauregui
authors.forename: Sandra
authors.initials: S
authors.lastname: Merscher-Gomez
authors.forename: Dony
authors.initials: D
authors.lastname: Maiguel
authors.forename: Cristina
authors.initials: C
authors.lastname: Muresan
authors.forename: Alla
authors.initials: A
authors.lastname: Mitrofanova
authors.forename: Ana
authors.initials: A
authors.lastname: Diez-Sampedro
authors.forename: Joel
authors.initials: J
authors.lastname: Szust
authors.forename: Tae-Hyun
authors.initials: TH
authors.lastname: Yoo
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Villarreal
authors.forename: Christopher
authors.initials: C
authors.lastname: Pedigo
authors.forename: R Damaris
authors.initials: RD
authors.lastname: Molano
authors.forename: Kevin
authors.initials: K
authors.lastname: Johnson
authors.forename: Barbara
authors.initials: B
authors.lastname: Kahn
authors.forename: Bjoern
authors.initials: B
authors.lastname: Hartleben
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Jharna
authors.initials: J
authors.lastname: Saha
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
mesh_terms: D000419:Albuminuria; D000818:Animals; D048429:Cell Size; D003928:Diabetic Nephropathies; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D060730:Glomerular Filtration Barrier / Q000166:cytology / Q000473:pathology; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D008070:Lipopolysaccharides; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D004317:Doxorubicin